We reported last year that inoculation of pathogenic sivmac into 2nd trimester rhesus fetuses or newborn infants resulted in rapidly fatal infection. In marked contrast, 2nd trimester or newborn inoculation of the molecularly cloned virus, sivmac1a11, resulted in transient infection without any clinical signs of disease in utero or after birth. Sivmac1a11 is an attenuated, nonpathogenic virus in immunocompetent juvenile and adult rhesus monkeys, and this virus is attenuated even in the immunologically immature fetal and newborn host. SIV-specific immune responses were measured in infants after sivmac1a11 inoculation. Antibody responses were detectable in all infants and levels persisted for more than 1 year. Weak SIV-specific CTL responses were detected at 2 or 4 months after birth and then became undetectable. This suggested that a pattern of split tolerance (positive antibody response but no CTL response) to siv may have occurred following infection of the immature host. To address this question, at approximately 1 year of age the infants were challenged by oral mucosal inoculation of pathogenic sivmac. After challenge by oral mucosal inoculation of pathogenic sivmac, 4 of 4 control infants became viremic and persistent infection was established. To our surprise, only 1 of 3 infants that were inoculated with sivmac1a11 in fetal life, and only 1 of 2 infants inoculated with sivmac1a11 at birth developed persistent infection and viral loads were low in comparison to those in control infants. Thus protective immunity and not classical tolerance resulted from fetal or newborn infection with an attenuated strain of sivmac. Recent evidence that some uninfected children of HIV-seropositive women have HIV-specific T cell immunity suggests that infection in utero or at birth with attenuated strains of HIV occurs and these children have acquired protective immunity.